Theoretical Immunology

[Leonard]

This thread breaks with the existing believe that MS is an autoimmune disease and on the way we found that micro-cellular nutrition is key. We also found that cortisol is probably not so much inflammatory suppressive but rather improves (the conditions for) micro-cellular nutrition which in turn calms down the immune system. This is probably one of the biggest dogma's in the medical world that will need to be relinquished..

We must not fall into the same trap as the medical world has done, that is that we start to believe dogmatically in certain concepts and thinking, for instance about the good and bad T-cells (see above posting of 4 June on diseases that originate from the gut). We must keep sight of new sources of inspiration and reference, we must cherish the means and preconditions to reinvigorate the sense of plurality. To this end, it is probably useful to halt for a moment here and ask ourselves the question why the immune system gets it wrong. And whether it is really true that bad T-cells get out of our gut to do their damaging work or, alternatively, whether these T-cells are just normal T-cells that for one reason or another are misguided, for instance by a deficiency in the nutrition.

From references above, it has been seen that the faulty gut may be the cause of a vast array of "immune" diseases. For some, the bad T-cells get to the joints and do their destructive work there leading to rheumatic diseases, or to the lungs leading to asthma; for others, the bad T-cells get on the glucose gates of our cells in a wider sense leading to diabetes mellitus type 2 with collateral damage to our myelin and Schwann cells leading to neuropathy. If we consider this case on its merits, a thesis could well be defended that argues that the T-cells are perfectly normal and re-active but that they are misguided in some way, that this can happen in different places in the body depending on genetic susceptibilities and predisposition, and possibly that the glucose metabolism is central and holds the key...

And there is evidence that would also suggest that if the normal glucose metabolism is restored (one way to express this would be to say "the insulin sensitivity is enhanced" but it is probably more than that), the immune system will calm down, the "bad" T-cells will start to behave normal, and the "immune" disease will be overcome..

Last night I searched a bit on the working mechanism of Metformin, the most common drug for diabetes mellitus type 2. What we do know is that it is not well understood how the drug works. The drug was derived from an old folks wisdom on the beneficial effects of the French lilac for people with diabetes and many mechanisms have been suggested since, some of which you may find in earlier postings on this thread. So I searched for Metformin, the glucose metabolism and the gut. And guess what? There is a strong suggestion here that Metformin works via the gut, in fact on the composition of the gut microbiota, see

http://www.trialregister.nl/trialreg/ad ... sp?TC=1775

Whow, this is big and would seem to bring things into line: It would suggest a central role for the glucose metabolism originating from the gut and explain why people with a gut flora transplantation may recover from diabetes and from MS, why people with diabetes mellitus type 2 benefit from Metformin and the progression of neuropathy comes to a halt.. And why people with MS…. To all, think it over...

But there was more. The search also brought up this paper on Metformin-induced regulation of the intestinal D-glucose transporters:

http://www.jpp.krakow.pl/journal/archiv ... rticle.pdf

We know that there is an important role for the gut and the liver in the glucose metabolism. The Million $ question now is: what is wrong with our glucose metabolism and probably related to this the fatty acid mechanism? What is it that misleads these T-cells? We know that it may be stopped by a new liver (re: Caucasian women with the new liver http://www.thisisms.com/forum/general-d ... c6044.html ). This last paper may hold a clue and should be explored with urgency.

[Leonard]

There are important issues here that need to be explored and investigated further as a matter of urgency. Endocrinologists, gastroenterologists, neuro-inflammatory experts and other medical specialists are much better trained and have a much deeper insight and better understanding (not necessarily always the right understanding) than me to do that. What is unfortunate and impedes progress in this matter is the prevailing culture and practices. I quote from:

http://www.demos.co.uk/files/publicvalueofscience.pdf

Market forces are dictating what is happening in the world of
higher education as never before. . . . Universities now
routinely operate complex patenting and licensing operations
to market their faculty’s inventions. . . . The question of who
owns academic research has grown increasingly contentious,
as the openness and shaping that once characterised university
life has given way to a new proprietary culture.

I have never felt so seriously competitive. . . . As patenting has
become so common, as industry has moved into the campuses, it is
competition, not cooperation, which is at a premium. Even within
the same lab, there can be Chinese walls between researchers
funded by different sponsors. We no longer speak openly about our
most recent work at scientific conferences, because to do so would
give our colleague-competitors a head start.

A fundamental challenge for any investigative field where entrenched hypotheses dominate care is to ensure that novel avenues of investigation remain open and productive; to lift barriers and cut red tape that may hamper effective progress. For that reason, a strong public engagement will be needed e.g. in future clinical trials design.

A pivotal issue seems what trials model to use to test the new insights. Most commonly practiced is a largely linear innovation model, conservative double blinded etc... For most people including for policy makers, that is easy to grasp intuitively, it feeds straight-forward almost literally. And there is an implied linearity in our own metaphor of the stream. Hence, the model in our laws and regulations is often based on this linear model.

But in our case, the model will depend nonlinearly on a set of parameters that may need to be taken into account and that can feed-back in many ways. Therefore, we must proceed iteratively to find the best or optimal solutions. We will need to build a new house that brings together all expertises required under one roof and pursue a nonlinear model that offers the flexibility needed. And we will need to do it fast.

And rather than seeing public engagement as a one-off fix, this matter will need a continuous public engagement throughout the complex and varied stages of innovation at different levels: specifically for our case (to solve MS with a sense of urgency) but also in a wider sense (to adapt the innovation model, to open it where needed, to make it fit for purpose for complex multi-facetted diseases). These seperate lines of action may mutually reinforce each other.

[Leonard]

This study http://insciences.org/article.php?article_id=10149 shows how quote: the make-up and the shape of a type of LDL cholesterol found in diabetics could make it more harmful than other types of LDL. Understanding exactly how ‘ultrabad’ LDL damages arteries is crucial, as this knowledge could help develop new anti-cholesterol treatments for patients. unquote To which I would add: .. it is most probably a whole lot more than just the arteries. It is the finest cappilaries, the veins, the lymphatic system... [added as an afterthought on 5 Nov 2012: The conclusions of this article http://care.diabetesjournals.org/content/24/8/1403.full seem to confirm just that: These mechanisms lead to artherosclerosis of the large arteries... Insulin resistance has been proposed to arise from similar pathogenic mechanisms in the peripheral arteriolar and capillary beds, with endothelial dysfunction... ]

The issue of the good and bad T-cells is related as this publication shows: http://www.sciencedaily.com/releases/20 ... 140048.htm quote: Scientists shed new light on link between ‘killer cells’ and diabetes... In the article on diabetes1, the killer T-cells attach to the pancreas, the killer T-cell receptor utilises an abnormal mode of binding in order to recognise cells producing insulin, and this unusual binding is thought to allow the T-cell to survive the culling process designed to rid the body of autoreactive T-cells.

Besides the possibility of directly binding T-cells, another more indirect scenario would seem possible as well as these articles show:
http://jaha.ahajournals.org/content/1/1/3.full#ref-12
http://www.ncbi.nlm.nih.gov/pubmed/2066 ... t=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/2042 ... t=Abstract

Although the focus is on atherosclerosis, coronary obstruction and the cardiovascular community, the articles suggest that:

- a false distinction is being made in the clinical and investigative communities between hyperlipidemia and inflammation as separate competing processes.
- the “lipid” and “inflammation” hypotheses may be more directly linked than previously appreciated
- observations identify the very early deposition of minimally modified LDL cholesterol as an “endogenous danger signal” capable of triggering interleukin-1β (member of lymphocyte-activating factor) and thus describe a new pathway by which cholesterol can directly induce a proinflammatory response
- it is worth to consider a unified hypothesis of cholesterol as a potential instigating factor for inflammation

If I combine the messages in the first two articles above (ultra bad cholesterol with diabetics; killer cells with diabetes; so an implied presumption of ultra bad cholesterol linked with killer cells) and with the line of thinking in the first posting on top of this page (T-cells misguided by the glucose metabolism), MGmin cholesterol may well be the culprit in the glucose metabolism that misguides the T-cells.

The third article would seem to support this idea that the “lipid” and “inflammation” hypotheses are linked but the mechanism of getting the T-cells out there may be a bit different [deposition of minimally modified LDL cholesterol as an “endogenous danger signal” capable of triggering interleukin-1β]. An important question is then: how is interleukin-1β triggered? I do not exclude the possibility here that there is an intermediate stage (the real cause) which is cellular nutrition / the glucose mechanism that fails because bad cholesterol impedes the nutrition process and 'blocks' glucose gates.

[ And that there is a relation with the glucose gates is obvious from the big temperature effect that pwMS experience. What also seems of particular interest here is that, allegedly, one of the many working mechanisms that have been attributed to Metformin is to 'enable' (a precursor of) the GLUTs (the glucose gates, there is an earlier posting on this thread). Now, it may well be possible that it is not the Metformin itself that enables the GLUTs but that the altered gut flora does something with the glucose metabolism that 'removes' ultrabad cholesterol from the bloodstream which, over time, will restore the normal functioning of the GLUTs. ]

Whatever the mechanism is (direct or indirect or both; type 1/type 2 might be related), Metformin that is known "to be able to break down MGmin cholesterol" (see earlier posting above) may well be a very useful drug that inhibits the gut from producing this ultra-bad and damaging form of cholesterol (we know it changes the gut flora, see above posting), of course in combination with diet. Or a gut flora transplant may do the same. The picture that emerges is complex and not easy to apprehend, and there may be better ways to express and explain it. But it seems to me that all pieces of the puzzle fit together neatly where we may have come to the root cause of progressive MS.


With that I think we are there!

[PointsNorth]

Leonard,

I want a signed copy of your book when it comes off the press

PN

[milesap]

Improved balance occurs in MS patients using counter weight vest
interesting video for those with balance problems:

http://balancewear.wordpress.com/2012/0 ... -the-news/
http://balancewear.wordpress.com/2012/0 ... developed/

[Leonard]

Sometimes I wondered whether I was perhaps getting a bit paranoia over this matter, whether I was living in a 'dream pipe' in the hope for a better life. But I know now that this was not a dream, that this is not some fantasy or delusion... Over the last year, I was introduced to the "medical system" and given some more insight. The information on this thread is real, the new concept is real, many links to new knowledge are real, and many of the connections made are correct and real…

Inevitably, as the boundary lines between my 'own world' and the medical world get thinner and become more permeable, I may find myself increasingly in more elective situations where our wider interests (i.e. for open dialogue, for finding a rapid solution for MS) get intertwined with positive steps taken in the medical world that I should not pre-empt or put at risk. No doubt the new situation will become a far-from-equilibrium phenomenon where the role of stakeholders will change and relate to differing challenges on a rapidly evolving basis. In this situation, I may have to observe a bit more restraint.

Why is this "alliance" with the medical world so important? We may shout it out from the highest towers, we may continue to cause ripples in the waters by our public patient fora and public advocacy groups and we should, we may seek contact with politics and the judicial system, but it is my assessment that that won't be enough. Change will have to come from within the sector. Information needs to be endorsed by doctors—or clinical bodies—that doctors trust; see e.g. http://blogs.bmj.com/bmj/2012/07/09/pri ... t-doctors/ And precisely that will happen… The medical sector will take its responsibility, possibly with political support… At this point, I can not promise you a solution for MS but what I can promise you is that things will change...

I know we are with many and I am one of you. If I take for a moment the countries of the North Atlantic alone, I count over 1 Million patients with MS, most probably well over 1 Million patients. And I know that many of us are desperately longing for a solution and the prospect for a better future, every day again. I am like that. So, if you see less from me over the next months, that doesn't mean that I have forgotten about our interests but rather that we need to give room to the sector to take its responsibility, to change the perception and the evaluation of MS data and set up new advanced schemes for clinical trials that work.

At this point in time, the best that each of you individually can do is to help grow a culture that requires neurologists and other professionals to let go of old knowledge as they acquire new, to unlearn as they learn.... Therefore, I urge each of you to ask your neurologist about new insights and possible new avenues for treatment and, if he/she does not know, to insist you get an answer… I count on your help…

[reallyreally]

I find Dr. Borody's work in Austrialia fascinating. In fact, I sent him my daughters medical records 9 years ago hoping he could help her. She was diagnosed with a gut disorder as an infant. Now, I have been re-reading about him and wondering if this could also help me now. I know some MS patients were treated with this. But, having a hard time finding follow up.
http://classic.the-scientist.com/news/display/57795/

[Leonard]

ADIOS MS

Now that there is ever more evidence that the old auto-immunity paradigm needs to be replaced by a new concept (see e.g. http://www.thisisms.com/forum/general-d ... 15188.html), let me offer you some thoughts on elements that may help reverse and overcome MS:

Angioplasty: to open up blocked veins in the drainage of the cerebro-spinal, could have preventive or pre-emptive effect for young people re: Zamboni's experience on Sardinia;
Anti-biotics: works for ealy onset/ young people diagnosed with MS caused by Cpn, there was a good study on this issue on http://www.msrc.co.uk a year or so ago.
This practice certainly delayed the onset of my own MS from 14 years of age (when first symptoms occured - loss of control of left hand) to 47 years of age (when diagnosed with MS). I must have been just lucky to get a good dose of anti-biotics when the first symptoms occured at 14 years of age (this was back in 1970 and then several times after with periods of 8/9 years in between) and - ironically- I must have been lucky that at that time we had a more rudimentary and technically less sophisticated health system. Because I "recovered" with the anti-biotics, I had a normal life and did not learn/know anything about MS until 47. Incidently, the diagnosis followed after a period of massive consumption of chocolates and sweets to prop up the system. With hindsight, this can all be explained: to prop up a weak glucose metabolism.. while growing the Clostrium family of bacteria in gut.
And I must have been lucky again: the last incident of the recurrent "bacteria-relapse" (was a small relapse with numbness of hands, in particular the left hand) was at 45, in the Spring, while the main relapse occured at 47, early Summer, just over two years after the small relapse. This meant that the 2 year-criterion for starting treatment with interferon was exceeded and therefore I never used interferon. Lucky, because the latest research shows that interferon with low vitamin D (which I developed) may have worked counterproductive, see e.g. http://www.msra.org.au/vitamin-d-and-in ... atments-ms
and where appropriate
Anti-virus medication in case MS is caused by EBV or other virus.

Diet: no/low sugar is essential for late onset or when in the progressive stage; not too much fat is indicated as well; fasting will help – in the extreme, it may even reverse diabetes; this is the track of Swank, Jelinek, Wahls and of that old wise neurologist -the craftsman- who advised his patients not to use sugar. And vitamin D supplementation that may cause many effects and help 'modulate' the immune system.

Intestinal tract and liver: feces transplantation may normalise the gut flora and the metabolic processes / glucose metabolism and -over time- remove ultra bad cholesterol that blocks nuclear receptors and -allegedly- is able to "feed badly trained T/B cells"; Metformin is a common diabetes type 2 medication that may have the same effect of stabilising the balance in the gut flora. [a new liver might as well reverse MS but that would seem a bit drastic]

[Olmesartan: this medication might possibly help to clean nuclear receptors in order that the glucose metabolism and transcription processes are strengthened; this is the track of Marshall.]

Support to insulin: e.g. Glimperide to support the insulin to get the glucose down into the cells, Glimperide is a common diabetes type 2 medication that may induce increased activity of intracellular insulin receptors, and apparently works in synergy with Metformin.

The letters make up the acronym ADIOS. The acronym is however NOT an invitation for yet another multi-annual research project or an old-style trials framework. The scale of the problem is so big while the elements being proposed would seem to be of relatively low risk, even if in combination [except then for the new liver but that is not really an option]. Therefore, according to the principle of proportionality – one of the leading principles in good governance, non-linear trial schemes should be promoted and enabled expeditiously that provide room to entrepreneurial doctors to make fast progress on this matter.

Let us just hope that the medical world supported by politics will be able to make this transition so that we may be able to say goodbye to MS in the not too distant future.

[reallyreally]

I saw this article last week and was interested in the relationship between MS and diabetes. The disappointing thing about this of course is because it is a "cure" wth an old drug there is no profit. So, finding funding has been difficult.

http://www.businessweek.com/news/2012-0 ... ine-for-tb

[Leonard]

I saw this article last week and was interested in the relationship between MS and diabetes. The disappointing thing about this of course is because it is a "cure" wth an old drug there is no profit. So, finding funding has been difficult.

http://www.businessweek.com/news/2012-0 ... ine-for-tb

thank you. The interesting point here is that a vaccine, a weakened form of the tuberculosis bacteria, does something for diabetes. It probably works in some way via the gut microbiota which is critical.

There is mounting evidence that alterations in the gastro-intestinal microbiota can affect immunologic diseases in humans, see e.g. http://web.inter.nl.net/users/vitaminda ... -in-ms.pdf

and that through administration of/exposure to micro-organisms and parasitic infections one is able to slow or prevent MS or 'autoimmune' reactions in general, see e.g. references 5 and 11 on http://www.charcot-ms.org/symposia/ecf- ... -2011.html (scroll a bit down...)

It all works via the gut. Gut microbiota is central to a whole range of chronic diseases and disease patterns. See also e.g. http://www.zeit.de/2012/17/M-Darm/seite-1

The link to this vaccine strengthens the whole gist of this thread... Thank you again.

[Leonard]

"Onset of progressive disease course seems to be age- rather than disease duration-dependent. "
re: http://www.ncbi.nlm.nih.gov/pubmed/22736750

This study result is VERY POWERFUL! It fully fits with the idea of a double underlying mechanism for MS as explained on this thread. It is a most clear confirmation for the new concept for MS as advocated by this thread.

[Leonard]

http://kirstyduncan.liberal.ca/blog/kir ... of-health/

the calm before the storm?

[Leonard]

Remarkable parallels between this cancer patient perspective under the link below and my own experiences for MS on this thread:

http://www.taxpayeraccess.org/perspecti ... mmer.shtml

I could fully support the call for open access to publicly financed research results from this side of the pond. Open access may lead to gains that cannot be measured in raw economic terms. I am sure that for MS -just like for cancer- open access will lead to greater patient-doctor communication, empowering patients to take a more active role in the management of their disease than has historically been possible. Clearly with risks attached to it but also with potentially great reward…


In this same context, this paper is of interest. It refers to the the Internet as "the most powerful infrastructure ever known for the creation, exchange and implementation of ideas". "It empowers the individual, and it empowers individuals who wish to work together." It is now such "a vibrant source of innovation" put "at the centre of driving economic growth and renewal."

http://papers.ssrn.com/sol3/papers.cfm? ... id=2104350

The focus of the paper is on ideas and opportunity "as the world embarks on rebooting economic activity". To which I would add the potentially huge benefits to society and patients as the medical world embarks on rebooting their vision on auto-immunity (and developing a unified theory of cholesterol as a potential instigating factor for inflammation).

For public policy makers who may find themselves increasingly in a juxta position between economic and consumer welfare, I would like to recall the words Francis Bator, the author of the Book The Anatomy of Market Failure (MIT Press), said already in 1958:
“Efficient markets may not do [give innovation beneficial to the extent that it enhances public values and equitable and positive social outcomes], efficiency of the ‘invisible hand’ does not preclude preference for other efficient modes of organization”.

[Leonard]

Why does MS onset extinguish above 60 years of age?
Because at that age people are diagnosed with diabetes type 2. When diagnosed with diabetes type 2, the regular diabetes treatment will help people to get control while any remaining symptoms will be attributed to the diabetes. In addition, the degree of vascular obstruction of the cerebro-spinal will be reasonably mild as otherwise the disease would have shown up as MS at a younger age.. There has been extensive discussion on this thread on the relation between diabetes and MS..

What explains the difference between men and women?
This is an issue to do with the hormones, in particular the influence of testosterone on the health of endothelial cells and its vasodilatory effects:
http://www.pnas.org/content/99/6/4055.full.pdf
quote: Results from our study may help explain the mechanism by which testosterone may have beneficial effect on the cardio-vascular system.
A higher level of testosterone in the blood is probably associated with a lower risk of getting MS (although that is just one factor)...

[added 8 Nov 2012: Testosterone shows nerve-protecting capabilities in mice with MS-like disease
http://www.msrc.co.uk/index.cfm/fuseact ... ageid/3524
although of course I don't agree with the EAE concept as such, my explanation here is that both for MS/glucose impairment and EAE, the vasodilatory effects of testosterone improve the nutritional condition of cells and hence provide nerve protection]

[added 30 March 2013: Testosterone Affects MS Outcomes in Men
http://www.thisisms.com/forum/general-d ... 21938.html ]

Toward proteomic and metabolic analyses ...
I don’t necessarily believe in all the highly complicated research papers. People are looking here into the astronomic complexity of our micro-cosmos that for most part -even today- remains in the dark. The large number of facets, peptides, enzymes, hormones, membranes, gut flora bacteria and antibiotics, inhibitors, and resulting therapeutic options come with an enormous complexity and technical limitations attached to it. As this paper on the gut microbiota rightly says, people better start to look into proteomic and metabolic analyses rather than classic microbiological techniques...by combining metagenomic and metabolomic studies:
http://www.nature.com/mi/journal/v4/n1/ ... 1079a.html

... and stabilisation of metabolic control ...
As this article says, it is all about the “stabilisation of metabolic control”. To this end, the article is useful as it explores the synergetic effects of combined standard diabetes type 2 medication namely Metformin / glimperide as well as Metformin / Gliptin for the management of diabetes 2.
http://www.thelancet.com/journals/lance ... 9/fulltext
We have seen before that Metformin works via the gut. I am getting convinced about the synergetic effects of combined metformin / glimperide and that this also works primarily via the gut.

... which will take time to take its full effect
The typical time constant for changes to the metabolic system (including in particular enhancing insulin sensitivity) may range from many months to several years (Swank characteristics; diabetes characteristics). As the above article rightly concludes, this would seem to imply that any future trial design for MS takes account of the typical long timespans involved including e.g. for long-term trials with incretin-based treatments. I find this wikipedia page is most instructive:
http://en.wikipedia.org/wiki/Incretin

I think we have pretty much unravelled MS and found plausible answers to virtually every question. What's more important: it all fits together in one bigger consistent picture. But here opens as well a new frontline in the discussion, on diabetes, glucose control, the role of the gut microbiota etc. I think that is now for professionals to pursue this work in a more coordinated effort...

[vesta]

I don't agree with the Diabetes theory at all. I don't have Diabetes. I think it's a question of blood circulation and cerebrospinal fluid circulation, both of which can be impeded by muscular stress. I agree there is too much complication. What if the main issue is simply the role of neck, shoulder and back tension on the veins leading from the brain and spinal cord (as noted by Dr. Zamboni et al) Apparently women have higher rates of MS than men between the onset of puberty and menopause. Maybe for women the role of monthly menstrual cramps is enough to compress the vascular system. Proper diet serves 2 functions, it removes stress from the vascular system and nourishes the CNS correctly. Maybe after age 60 there are fewer MS onset cases because the candidates are dead. (Or retired and subject to less stress. Yes, there is the hormonal factor which may stress -or enhance- the vascular system as well.) Anyway, I think the Chinese Medicine observation that MS treatment involves balancing the meridians beginning on the head and running down the neck, shoulder and /or back (gall bladder and bladder) says something about the root cause of MS. See MS Cure Enigmas.net